The goal of the current Grand Opportunity is to create a unique, multimodal transcriptional atlas of the pre- and postnatal developing human brain. To achieve this ambitious goal in two years, we propose to bring together expertise in human and non-human primate brain development (Sestan, Yale;Lein, Allen Institute), MRI and DTI imaging (Fischl, Harvard/MGH), large-scale transcriptional profiling (Sestan, Yale;Geschwind, UCLA), and the resources of the Allen Institute for Brain Science and Yale University in bioinformatics, information technology, industrial scale histological data generation and atlas generation, and transcriptome analysis (Lein, Hawrylycz, Allen Institute;Sestan, Gerstein, Yale). Members of this consortium will contribute key data components of the atlas using their existing core capabilities at scale, which will be integrated through a powerful public access web-based portal for viewing, searching and mining of spatiotemporal gene expression patterns in the anatomical context of human brain development. The Allen Institute will create an atlas framework, consisting of a set of de novo multimodal imaging and histological reference atlases spanning human brain development, and a complete informatics structure for mapping, integrating, and presenting transcriptional data in the context of neuroanatomical structure and key developmental events. Contributing laboratories will generate transcriptional data utilizing cutting edge profiling techniques applied at the largest feasible scale, including microarray analysis across the entire fetal brain, RNA-seq deep sequencing data to provide comprehensive genomic coverage in targeted cortical and subcortical structures across 12 developmental stages (Sestan, Yale), and celular resolution data to validate and extend the profiling data and to aid interpretation of dynamic spatiotemporal gene expression patterns. Specifically, the Allen Institute will create or manage generation of 1) 12 new MRI, diffusion tensor imaging (DTI) and histological digital annotated reference atlases spanning human brain development, 2) an anatomically comprehensive microarray analysis of early to mid-fetal brains, with sophisticated visualization and analysis tools and a complementary ISH follow-up data set, 3) a celular resolution ISH atlas of gene expression spanning postnatal brain development, mirroring the ongoing NIH Blueprint rhesus macaque neurodevelopmental atlas, and 4) a new web-based portal for presenting and linking all data modalities, including a massive transcriptome analysis of targeted brain regions spanning human brain development generated by the Sestan laboratory. All of these data will be integrated through the centralized web portal, and linked to a series of similar data resources allowing direct comparative analysis between human, non-human primate and rodent model systems. This portal will create a long-lasting resource for the scientific and medical research communities for relating specific transcriptional programs to processes of human brain development. PUBLIC HEALTH RELEVANCE: The current proposal describes the creation of a new and unique data-rich resource integrating transcriptomic, cellular resolution histology and imaging data in the context of human brain developmental mechanisms through a powerful, easy to use public access web-based portal for viewing, searching and sophisticated mining of spatiotemporal gene expression patterns. The final product, consisting of new reference atlases spanning pre- and postnatal human brain development, systematic and comprehensive transcriptome analysis, large-scale cellular resolution analysis, a variety of tools for visualization and data analysis, and extensive linking to external resources, will create a long-lasting resource for relating specific transcriptional programs to processes of human brain development.